Background. Analyte specificity and sensitivity for biosensing in general and multiplexed sensing of biomedically relevant compounds must be improved to provide clinical utility for these devices. In particular, improvement of sensor signal while limiting noise are two important performance enhancements sought with improved designs. This proposal is motivated by our observations that (1) immunobiosensing represents the most commonly exploited and developed bioanalytical device for non-invasive and invasive biomedical diagnosis; (2) detection limits for analytes scale with immunosensing array size; (3) submicron optical waveguides represent a technical frontier for this sensing modality; (4) advantages of reducing size scale in optical waveguides are feasible with a paradigm shift in this sensing device design. Hypothesis. To address these challenges, we propose our working hypothesis that increased bioananalyte sensitivity and device response for multianalyte sensing in complex milieu (e.g., physiological fluids, saliva, and serum) will be gained by integrating a new optical sensing mode with miniaturization of sensing components to the sub-micron scale. This hypothesis involves integrating issues of device scale (transport, arraying, optical reporting) with new optical waveguide device modalities appropriate for sensing constructs fabricated in this size scale Specific Aims. To test and validate our hypothesis, we propose the following five Specific Aims: Aim 1: Define by optical theory a mode for reagentless evanescent detection in this model; Aim 2: Use fluid transport theories to support rapid response and detection kinetics and waveguide sensing performance enhancements expected for this device operating in these small size (sub-micron) optical and fluid mechanical scales; Aim 3: Establish a functional prototype integrated optical waveguide sensing device based on a new submicron waveguide method and microarrayed immunoprobe regions specific for different analytes; Aim 4: Integrate NSOM far-field optics as a detection technology into a waveguide device for sub-micron evanescent sensing; Aim 5: Establish working bioanalytical definitions for sensitivity limits, detection, and kinetic response for four model analyte classes--small molecules, proteins, viruses, and DNA--using this device in complex fluid milieu relevant to physiological based sensing.